Non-small cell lung cancer (NSCLC) is the most common cause of cancer death in the U.S. Most NSCLC patients die of recurrent progressive disease after primary therapy. There are no available therapies for recurrent lung cancer associated with long-term disease-free survival. New therapies for NSCLC, particularly for recurrent disease, are a critical need. Epigenetic gene silencing mediated through aberrant DNA methylation and histone deacetylation is a key contributor to lung carcinogenesis. Preclinical studies by our group have shown that combined inhibition of DNA methyl transferases (DNMT) and of histone deacetylases (HDAC) synergistically induces re-expression of tumor suppressor genes epigenetically silenced in cancer. Clinical studies at our institution of the DNMT inhibitor 5AC in combination with HDAC inhibitors phenylbutyrate or MS- 275 in hematologic malignancies have resulted in remarkable clinical activity associated with reversal of epigenetic changes in key tumor suppressor genes silenced in these diseases. We propose to test the efficacy of combined epigenetic targeting in patients with advanced, recurrent NSCLC using 5AC and MS-275 on a schedule shown to be well-tolerated and associated with significant activity in patients with hematologic malignancies. The trial will include correlative analyses designed to evaluate whether therapy is associated with re-expression of genes we have found to be frequently epigenetically silenced in lung cancer. The aims of this project include the following: SA1: To assess safety, characterize toxicities, and determine the maximum tolerated dose of 5AC with MS-275 in patients with recurrent advanced NSCLC. SA2: To determine the objective response rate of 5AC and MS-275 in patients with recurrent NSCLC. SA3: To determine the pharmacokinetic profile of 5AC and MS-275 in patients with recurrent NSCLC. SA4: To assess the pharmacodynamic effects of 5AC and MS-275 on DNA methylation, histone acetylation, and gene re-expression in patients with recurrent NSCLC through analysis of blood, sputum and tissue biopsies. Lung cancer is the most common cause of cancer death in both men and women, responsible for over 160,000 deaths annually in the U.S. This project will study a novel therapeutic strategy in patients with lung cancer, based on reversing the aberrant silencing of regulatory genes in cancers. If successful, this approach could alter the poor prognosis of individuals with this disease. [unreadable] [unreadable] [unreadable]